It is well established that the primary modes of altering myocardial contractility on a beat-to-beat basis involve both the modulation of the myoplasmic Ca2+ availability at the level of the myofilaments (MF), and changes in the Ca2+-response of the MF, especially via length-dependent activation. Fundamental aspects of how myocardial stretch increases contractile force remain obscure. Myocardial stretch was found to modulate the elementary Ca2+-release process from ryanodine-receptor Ca2+-release channels (RyRC), known as Ca2+-sparks. Ca2+-spark frequency in cardiac myocytes varied directly with stretch from sarcomere lengths (SL) 1.8 mum to 2.1 mum, without changes in individual-Ca2+-spark kinetics. These stretch-related phenomena were abolished by the specific NOS-inhibitor, L-NAME. Pulse application of the NO-releasing agent, SNAP, reversibly increased Ca2+-spark frequency at slack SL. Pursuing these mechanisms of stretch-induced changes in intact heart, the Frank-Starling response was found to be substantially blunted in hearts from aged (24 month) compared to that from young (6-8 month) rats. Furthermore, the slope of the Frank-Starling curve, while reduced by about 25-35% in the presence of L-NAME in the young rat heart, is almost entirely flat in the old rat heart. It is proposed that the endogenous production of NO plays a physiological role in heart as a second messenger of stretch which enhances RyRC activity contributing to myocardial contractile activation. NOS-3, the likely source of this NO, is a candidate stretch sensor; its caveolar-compartmentalization adjacent to the SR-T-tubule junction could result in NO production and effects localized at the site of RyRCs. Thus, cardiac stretch recruits additional contractile reserve in part via enhancement of the SR Ca2+-release process mediated by the endogenous production of NO. Endogenous NO may play a particularly important role in aged myocardium by moderating the susceptibility to heart failure in spite of the extant loss of other mechanisms of contractile reserve.